Pyrazolo(3,4-d)pyrimidine derivatives

ABSTRACT

NEW PYRAZOLO(3,4-D)PYRIMIDINE DERIVATIVES WHICH HAVE THE FORMULA   1-R1,3-R3,4-(R-O-),6-R2-1H-PYRAZOLO(3,4-D)PYRIMIDINE   WHEREIN R IS HYDROGEN OR LOWER ALKYL, R1 IS LOWER ALKYL, CYCLOALKYL, PHENYL OR SUBSTITUTED PHENYL, R2 IS CYCLOALKYL, PHENYL OR SUBSTITUTED PHENYL AND R3 IS HYDROGEN, LOWER ALKYL, CYCLOALKYL, PHENYL OR SUBSTITUTED PHENYL, AND SALTS THEREOF, ARE USEFUL AS HYPOGLYCEMIC AGENTS AND ANTI-INFLAMMATORY AGETS.

United States Patent 3,732,225 PYRAZOL0[3,4-d]PYRIMIDINE DERIVATIVESHermann Breuer, Burgweinting, and Uwe D. Treuner and Ernst Schulze,Regensburg, Germany, assignors to E. R. Squibb & Sons, Inc., New York,N.Y. N0 Drawing. Filed July 23, 1970, Ser. No. 57,828 Int. Cl. C07d /46U.S. Cl. 260256.4 F 4 Claims ABSTRACT OF THE DISCLOSURE Newpyrazolo[3,4-d1pyrimidine derivatives which have the formula wherein Ris hydrogen or lower alkyl, R is lower alkyl, cycloalkyl, phenyl orsubstituted phenyl, R is cycloalkyl, phenyl or substituted phenyl and Ris hydrogen, lower alkyl, cycloalkyl, phenyl or substituted phenyl, andsalts thereof, are useful as hypoglycemic agents and anti-inflammatoryagents.

SUMMARY OF THE INVENTION This invention relates to newpyrazolo[3,4-d1pyrimidine derivatives which have the formula and saltsthereof.

The symbols have the following meanings in Formula I and throughout thisspecification.

R is hydrogen or lower alkyl, R, is lower alkyl, cycloalkyl, phenyl orsubstituted phenyl, R is phenyl, substituted phenyl or cycloalkyl and Ris hydrogen, lower alkyl, cycloalkyl, phenyl or substituted phenyl. Thelower alkyl groups represented by R and R are straight or branched chainhydrocarbon groups of up to seven carbon atoms, e.g., methyl, ethyl,propyl, butyl, t-butyl and the like, methyl and ethyl being preferred.The cycloalkyl groups are cyclo-lower alkyl groups of three to sevencarbon atoms, especially cyclohexyl. The substituted phenyl groups,i.e., R -phenyl, are those bearing a halogen, preferably chlorine orbromine, a lower alkyl group of the type referred to previously,preferably methyl or ethyl, or a lower alkoxy group, eg, methoxy, ethoxyor the like, in one of the positions on the ring.

Preferred are those compounds wherein R is lower alkyl, especiallyethyl, R is methyl and R is phenyl, chlorophenyl, especiallyp-chlorophenyl, or cyclohexyl and R is hydrogen or lower alkyl,especially the first.

When R is hydrogen, the compounds of Formula I may tautomerize so thatthe tautomeric variations of such compounds are also within the scope ofthe invention.

The compounds of Formula I form salts with strong acids and these arealso within the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION The compounds of Formula I arederived from intermediates of the formula 3,732,225 Patented May 8, 1973wherein X is halogen, preferably chlorine, and R R and R are as definedpreviously, by treating such an intermediate with an alkali metalalkoxide such as sodium methylate, sodium ethylate and the like in analcohol having the same alkyl group, e.g., methanol, ethanol, etc., orin an inert solvent like benzene, toluene, dimethylformamide ordimethylsulfoxide. This produces a compound of Formula I wherein R is alower alkyl group (corresponding to the alkyl group of the alkali metalalkoxide) and R R and R are the same groups as in the intermediate ofFormula II.

This product may be converted to one in which R is hydrogen (or itstautomeric keto form) by hydrolysis with a hydrohalic acid such ashydrobromic or hydroiodic acid.

The intermediate of Formula II may be derived by several syntheticroutes. The following reaction sequence is illustrative of one method ofsynthesis. It will be appreciated that the particular reactant, reagentor medium indicated is illustrative and is not the only one which may beused, but common variants may also be used.

The symbols, R, R R and R have the meanings already defined.

toluene An alternate synthesis of an intermediate of Formula VIIincludes the following reaction sequence:

R: C0001H5 CzHsOH (3211 0 =0 HrN-NH-Rr or other CEN alcohol (VIII) acidbinding agent O i l R; OC2H5 NHa R3 NH iii JLNH C R -10 atm. 1 I R I I180200 N I A l R1 R;

The compound of Formula VII is then treated with POCl and PCl as in theprevious method.

According to still another alternative a compound of Formula V isconverted to a compound of Formula VII as follows:

and the compound of Formula VII is further treated with POCIg and PCl asabove.

The compounds of Formula I form acid addition salts with strong organicor inorganic acids, e.g., hydrohalic acids, especially hydrochloric andhydrobormic acids, sulfuric acid, nitric acid, phosphoric acid,methanesulfonic acid, toluenesulfonic acid, etc. These are formed byreacting the base with an equivalent amount or excess of the acid. Thesesalts frequently provide a means of isolating the product, e.g., byforming the salt in a solvent in which it is insoluble. The isolatedsalt may then be converted to the free base, e.g., by neutralizationwith a base such as sodium or barium hydroxide, and, if desired, anothersalt then may be formed.

The new compounds of this invention have anti-inflammatory propertiesand are useful as anti-inflammatory agents, for example, to reduce localinflammatory conditions such as those of an edematous nature orresulting from proliferation of connective tissue in various mammalianspecies such as rats, dogs and the like when given orally in dosages ofabout 5 to 50 mg./kg./day, preferably 5 to 25 mg./kg./day, in single or2 to 4 divided doses, as indicated by the carageenan edema assay inrats. The active substance may be utilized in compositions such astablets, capsules, solutions or suspensions containing up to about 300mg. per unit of dosage of a compound or mixture of compounds of FormulaI or physiologically acceptable acid addition salt thereof. They may becompounded in conventional manner with a physiologically acceptablevehicle or carrier, excipient, binder, preservative, stabilizer, flavor,etc. as called for by accepted pharmaceutical practice. Topicalpreparations containing about 0.01 to 3 percent by weight of activesubstance in a lotion, salve or cream may also be used.

The compounds of this invention also are hypoglycemic agents which areeffective in lowering blood sugar content in mammalian species such asmice, rats, rabbits, dogs or the like in a manner analogous totolbutamide. Some are particularly noteworthy in their long duration ofaction. For this purpose a compound or mixture of compounds of FormulaI, or non-toxic, physiologically acceptable acid addition salt thereof,may be administered orally or parenterally in a conventional dosage formsuch as tablet, capsule, injectable or the like. A single dose, orpreferably 2 to 4 divided daily doses, provided on a basis of about 1 to50 mg. per kilogram per day, preferably about 2 to 15 mg. per kilogramper day, is appropriate. These y be conventional y formu a ed in an oralor parenteral dosage form by compounding about 10 to 250 mg. per unit ofdosage with conventional vehicle, excipient, binder, preservative,stabilizer, flavor or the like as called for by accepted pharmaceuticalpractice.

The following examples are illustrative of the invention. Additionalmembers are produced in the same manner by approprate variations of thegroups, R, R R and R in the reactants used. All temperatures are on thecentigrade scale.

EXAMPLE 1 1-methyl-4-cyano-5-aminopyraz0le To a solution of 70 grams of98% methyl hydrazine and 700 ml. of ethanol are added altogether 127gms. of ethoxymethylene malononitrile in such a manner that the solutionremains at the boiling point. After completion of the addition, thereaction mixture is heated to reflux for 30 minutes. The product ispermitted to crystallize overnight in the refrigerator. After filteringunder suction and washing with a small amount of cold ethanol, 103 gms.of crude 5-amino-4cyano-1-methylpyrazole remains as yellow crystals,M.P. 216-218. This product is then used further without recrystallizing.

EXAMPLE 2 1-methyl-4-eyano-S-benzoylaminopyrazole EXAMPLE 31-methyl-6-phenylpyrazolo 3,4-d] pyrimidin-4-one 29 grams of1-methyl-4-cyano-S-benzoylaminopyrazole, 450 ml. of 3% hydrogen peroxideand 13 gms. of potassium hydroxide are heated for 5 hours at 7075. Aftercooling, the mixture is acidified with glacial acetic acid. A thickwhite precipitate forms which is washed with ice-water and thenrecrystallized from ethanol. The1-methyl-6-phenylpyrazolo[3,4-d]pyrimidin 4-one melts at 250-252.

EXAMPLE 4 1-methyl-4-chloro-6-phenylpyrazolo[3,4-d] pyrimidine 2 gramsof l-methyl-6-phenylpyrazolo[3,4-d]pyrimidin- 4-one are heated at refluxfor 3 hours in 20 ml. of phosphorous oxychloride. The excess phosphorousoxy chloride is distilled olf and there remains an oil which slowlycrystallizes. The crystals are washed with icewater, dried andrecrystallized from cyclohexane. The pure compound melts at 110-111.

EXAMPLE 5 1-methyl-4-ethoxy-6-phenylpyrazolo[3,4-d]pyrimidine 4.9 gms.of 1-methyl-4-chloro-6-phenylpyrazolo[3,4-d] pyrimidine in ml. of anethanol solution containing 20 ml. of sodium ethylate are heated atreflux for 30 minutes. After cooling, the mixture is diluted with waterwhereupon white crystalline1-methyl-4-ethoxy-6-phenylpyrazolo[3,4-d]pyrimidine precipitates. Uponrecrystallization from ethanol, there are obtained white crystalsmelting at 83-89. Hydrolysis of this product with 40% hydrogen bromidegives 1-methyl-6-phenyl-lg-pyrazolo [3,4-d1pyrimidin-4-ol, M.P-250-252".

EXAMPLE 6 1-methyl-4-cyano-5-(p-chlorobenzoyl)aminopyrazole Bysubstituting p-chlorobenzoyl chloride for the ben- 6 EXAMPLE 111-methyl-fi-cyelohexylpyrazolo[3,4-d] pyrimidin-4-one By treating theproduct of Example according to zoyl chloride in the procedure ofExample 2, there is 5 the d e proce ure of Example 3, the above product1s obobtamed (p'chlorobenzoynoanuno' tained in the form of whitecrystals, M.P. 242-244. pyrazole 1n the form of white crystals, MP. 182

EXAMPLE 12 EXAMPLE 7 m l-methyl-4-chloro-6-cyclohexylpyrazolo1-methy1-6-p-chlorophenylpyrazo1o[3,4-d] P ri idi -tp By treating theproduct of Example 11 according to the procedure of Example 4, the aboveproduct is obtained Y utlhzmg the Product of Elfample 1n the Procedureas white crystals which are recrystallized from n-hexane, of Example 3,there are obtained whlte crystals of l- 15 M P 7 methyl 6-pchlorophenylpyrazolo[3,4-d1pyrimidin-4- 1 EXAMPLE 13 one, which arerecrystallized from methylene glycol, M.P. 290.l-methyl-4-ethoxy-6-cyclohexylpyrazolo EXAMPLE 8 BA-Mpy i By treatingthe product of Example 12 according to g?: i qgi the procedure ofExample 5, l-methyl-4-ethoxy-6-cyclolpymm mehexylpyrazolo[3,4-d]pyrimidine is obtained in the form By treating theproduct of Example 7 according to of light yellow crystals, M,P. 47. theprocedure of Example 4, there is obtained l-methyl- 6-cyclohexyll-methyl-lg-pyrazolo[3,4-d]pyrimidin- 4-chloro6p-chlorophenylpyrazolo[3,4-d] pyrimidine in 4'01 is obtained from theforegoing product by hydrolysis the the formof white crystals which arerecrystallized with hydrobromic acid, M.P. 242244. from cyclohexane,M.P. 162-164". The following additional products are obtained by theprocedure of Example 5: l

11 n1 R1 R3 Example 16 01H: GaHs ciHs E Q Q} Q 18 Q Q CH3 Br Br 9 CzHsCH: Q E

om-Q- out-- EXAMPLE 9 What is claimed is:1-methyl-4-ethoxy-6-p-chlorophenylpyrazolo A compound of the formula[3,4-d1pyrirnidine By treating the product of Example 8 according to theO-lower alkyl procedure of Example 5,1-methyl-4-ethoxy-6-p-chlorophenylpyrazolo[3,4-d]pyrimidine is obtainedas white Rs crystals which are recrystallized from cyclohexane, M.-P. I128-129. ,J-R:

EXAMPLE 10 N 1-methyl-4-cyano-5-(cyclohexylcarbonylamino)pyrazole Byutilizing 1-methyl-4-cyano-5-amino pyrazole and wherein R is loweralkyl, cycloalkyl of 3 to 7 carbon cycyohexanecarbonyl chloride in theprocedure of Examatoms or phenyl, R is cycloalkyl of 3 to 7 carbonatoms, ple 2, 1-methy1-4-cyano-5-(cyclohexylcarbonylamino) and R ishydrogen, lower alkyl, cycloalkyl of 3 to 7 pyrazole is obtained aswhite crystals, which are recarbon atoms or phenyl and physiologicallyacceptable crystallized from methanol, M.P. 163-165. acid addition saltsthereof.

7 8 2. A compound as in claim-1 wherein R is cyclohexyl. FQREIGN PATENTS3. A compound as in claim 1 wherein R is lower alkyl 937,723 9/1963Great Britain.

R is cyclohexyl.

4. A compound as in claim 1 wherein the lower alkyl ALEX MAZEL primaryExaminer 'thl,R' thl dR'hd group is e y 1 is me y an I 3 15 y rose 5 R.V. RUSH, Assistant Examiner US. Cl. X.R.

References Cited UNITED STATES PATENTS 2,965,643 12/1960 Druey et al.260--256.4 0 3,211,732 10/1965 Schmidt et al 260256.4 1

